Leukotrienes are a family of lipid mediators derived from arachidonic acid (ARA) through the 5-lipoxygenase pathway. They are produced by various leukocytes, hence the first part of their name (leuko-). The tri-ene part of the name refers to the number (three) of conjugated double bonds (alkenes). Examples of leukotrienes are LTA4, LTE4, LTC4, LTD4, LTE4, and LTE4, with LTC4, LTD4 and LTE4 often called cysteinyl leukotrienes (CysLTs) due to the presence of the amino acid in their structure. The first leukotriene to be synthesized, leukotriene A4 (LTA4), is formed through conversion of ARA located in membrane phospholipids to 5-hydroperoxyeicosatetraenoic (5-HPETE) and LTA4 through membrane-bound 5-lipoxygenase and 5-lipoxygenase-activing protein (FLAP). In human mast cells, basophils, eosinophils, and macrophages, LTA4 converts quickly to either LTE4 (through LTA hydrolase) or LTC4 by LTC4 synthase with the incorporation of glutathione (γ-glutamyl-cysteinyl-glycine). LTC4 is subsequently converted to LTD4 and then to the stable end product LTE4 (FIG. 1) (Rabinovitch, N. Urinary Leukotriene E4. Immunol. Allergy Clin. N. Am. 27:651-664, 2007 and Busse W, Kraft M. Cysteinyl leukotrienes in allergic inflammation: strategic target for therapy. Chest 2005; 127:1312-26).
The CysLTs are important mediators of inflammatory reactions and exert powerful effects on vasoconstriction and bronchoconstriction (Doucet M Y, Jones T R, Ford-Hutchinson A W. Responses of equine trachealis and lung parenchyma to methacholine, histamine, serotonin, prostanoids, and leukotrienes in vitro. Can J Physiol Pharmacol 1990; 68:379-83; Gyllfors P, Kumlin M, Dahlén S E, Gaber F, Ehrs P O, Dahlen B. Relation between bronchial responsiveness to inhaled leukotriene D4 and markers of leukotriene biosynthesis. Thorax 2005 November; 60(11):902-8). CysLTs are thus mediators of inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease (Busse W, Kraft M. Cysteinyl leukotrienes in allergic inflammation: strategic target for therapy. Chest 2005; 127:1312-26; Kanwar S, Johnston B, Kubes P. Leukotriene C4/D4 induces P-selectin and sialyl Lewis (x)-dependent alterations in leukocyte kinetics in vivo. Circ Res 1995; 77:879-887). In particular, CysLTs have been implicated in asthma worsening triggered by exposure to tobacco smoke.
Clinical studies have demonstrated that leukotriene receptor antagonists (LTRAs) are able to reduce rescue treatment requirements, improve pulmonary function and reduce symptoms in adults and children with asthma (Barnes N, Thomas M, Price D, Tate H. The National Montelukast Survey. J Allergy Clin Immunology 2005; 115; 47-54; Becker A, Swern A, Tozzi C A, Yu Q, Reiss T, Knorr B. Montelukast in asthmatic patients 6 years-14 years old with an FEV1>75%. Curr Med Res Opin 2004 October; 20 (10): 1651-9). This relationship between CysLTs and asthma severity appears to not be homogenous across populations. For example, a number of studies have reported that female schoolchildren respond more favorably to the LTRA montelukast than boys (Szefler S J, Phillips B R, Martinez F D, Chinchilli V M, Lemanske R F, Strunk R C, et al. Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol 2005; 115:233-42; Johnston N W, Mandhane P J, Dai J, Duncan J M, Greene J M, Lambert K, et al. Attenuation of the September epidemic of asthma exacerbations in children: a randomized, controlled trial of montelukast added to usual therapy. Pediatrics 2007 September; 120(3): 702-12) and that smoking adults show a greater response than non-smokers (Lazarus S C, Chinchilli V M, Rollings N J, Boushey H A, Cherniack R, Craig T J, et al. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med 2007 Apr. 15; 175 (8): 783-90). Other studies have reported both that urinary LTE4 excretion increases acutely after tobacco smoking (Fauler J, and Frolich J C. Cigarette smoking stimulates cysteinyl leukotriene production in man. Eur J Clin Invest 1997; 27:43-47.) and that levels of FENO are lower in schoolchildren with chronic environmental tobacco exposure (Warke T J, Mairs V, Fitch P S, Ennis M, Shields M D. Possible association between passive smoking and lower exhaled nitric oxide in asthmatic children. Arch Environ Health 2003 October; 58(10): 613-6; and Nordvall S L, Janson C, Kalm-Stephens P, Foucard T, Torén K, Alving K. Exhaled nitric oxide in a population-based study of asthma and allergy in schoolchildren. Allergy 2005 April; 60(4): 469-75.). Why antileukotriene medications are effective in some subjects and ineffective in others remains unclear. Some studies suggest that susceptibility to LTRAs is related to differences in CysLT levels between individuals (Szefler S J, Phillips B R, Martinez F D, Chinchilli V M, Lemanske R F, Strunk R C, et al. Characterization of within-subject responses to fluticasone and montelukast in childhood asthma. J Allergy Clin Immunol 2005; 115:233-42; Cai C, Yang J, Hu S, Zhou M, Guo W. Relationship between urinary cysteinyl leukotriene E4 levels and clinical response to antileukotriene treatment in patients with asthma. Lung 2007 March-April; 185(2): 105-12) while other studies have not observed this relationship (Dahlén S E, Malmstrom K, Nizankowska E, Dahlén B, Kuna P, Kowalski M, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist. A randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165: 9-14). As such, it is unclear whether susceptibility is primarily a function of increased CysLT production, differences in pharmacokinetic metabolism of the medication, increased receptor sensitivity or perhaps a more complex interaction with other mediator pathways. Identifying biological and phenotypic characteristics related to CysLT effects and efficacy of LTRAs such as montelukast would allow for more defined clinical evaluations focused on subpopulations most likely to benefit from such treatments.
In previous studies, the relationship between the stable end-product of CysLT metabolism, leukotriene E4 (LTE4) and asthma control was examined (Rabinovitch N, Zhang L, Gelfand E W. Urine leukotriene E4 levels were determined to be associated with decreased pulmonary function in children with persistent airway obstruction. J Allergy Clin Immunol 2006 September; 118 (3): 635-40).
While inhaled corticosteroids (ICS) are generally considered more potent than LTRAs and are therefore recommended as first-line therapy (Ducharme F M, Di Salvio F. Anti-Leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. The Cochrane Database of Systematic Reviews 2004, issue 1, Art. No. CD002314) treatment with ICS alone may not adequately control disease in 30% to 40% of patients (Heaney L G, Robinson D S. Severe asthma treatment: need for characterising patients. Lancet. 2005 Mar. 12-18; 3 65(9463): 974-6). This could reflect the inability of ICS therapy to reduce leukotriene production in certain subject subsets where this pathway predominates (Manso G, Baker A J, Taylor I K, Fuller R W. In vivo and in vitro effects of glucocorticosteroids on arachidonic acid metabolism and monocyte function in nonasthmatic humans. Eur Respir J 1992; 5:712-6; O'Shaughnessy K M, Wellings R, Gillies B, Fuller R W. Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion. Am Rev Respir Dis 1993; 147:1472-6). Although previous reports suggest that LABAs (long-acting beta-agonist) are superior to LTRAs in combination therapy (Ram F S F, Cates C J, Ducharme F M. Long acting beta-2 agonists versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma. The Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No. CD003137), other studies have reported that the addition of montelukast to ICS therapy is similar to LABAs in reducing symptoms and exacerbations of asthma (Ilowite J, Webb R, Friedman B, Kirwin E, Bird S R, Hustad C M, et al. Addition of montelukast or salmeterol to fluticasone for protection against asthma attacks: a randomized, double-blind, multicenter study. Ann Allergy Asthma Immunol 2004 June; 9 2(6): 641-8; Bjermer, L, Bisgaard H, Bousquet, J, Fabbri L M, Greening A P, Haahtela, T, et al. Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomized, comparative trial. BMJ 2003; 327:891).